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HEREDITARY MONOGENIC DISEASES

           

Very long chain acyl-CoA dehydrogenase deficiency (VLCADD)

Very long chain acyl CoA dehydrogenase deficiency (VLCADD) is an inherited disorder of the mitochondrial oxidation of long chain fatty acids with variable phenotypes which include: cardiomyopathy, hypocetotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis.

In total about 400 cases have been described worldwide.

VLCADD is caused by mutations in the ACADVL gene (17p13.1). Mutations in this gene cause dysfunction of mitochondrial beta-oxidation of long chain fatty acids.

VLCADD is a clinically heterogeneous disease with three main phenotypes:

  1. Severe infant VLCADD has an early onset, from the neonatal period to the first 3-12 months. It has a high mortality rate and a high incidence of hypocetotic hypoglycemias, liver disease, cardiac arrhythmias, pericardial effusions and cardiomyopathies.
  2. Moderately severe childhood VLCADD has a later debut. Hypocetotic hypoglycemia can be observed, and, rarely, cardiomyopathy. Low mortality.
  3. Late-onset myopathic VLCADD can be observed in older children (10 years old or more). It affects skeletal muscles, and causes intolerance to physical exercise, myalgia, rhabdomyolysis and myoglobinuria (normally triggered by physical exercise), fasting, heat or cold or aggressions, although viral infections can also cause or speed up the process. Rarely, renal failure can occur, which can be fatal.

VLCADD is confirmed by identifying two pathogenic mutations in the ACADVL gene.

An abnormal acylcarnitine profile in blood or plasma identifies virtually all patients with severe or moderately severe phenotypes by showing an increase in C14:1 and the C14:1/C12:1 ratio along with an increase in C12, C16, C16:1, C18 and C18:1. Occasionally, patients with fundamentally myopathic conditions may have a normal profile when they are metabolically stable.

VLCADD is inherited as an autosomal recessive character and there is the possibility of genetic counseling. It is possible to make a prenatal diagnosis when mutations in the family have been identified.

It is essential to strictly avoid fasting in children. The diet should be low in long chain fats and should be combined with the intake of medium chain triglycerides. If there are signs of decompensation, a special medical treatment and diet should be applied immediately for these situations. Bezafibrate treatment offers a potential benefit in myopathic patients with residual enzyme activity, although a thorough clinical evaluation is necessary.

VLCADD can be deadly, but thanks to neonatal screening programs, evolution is improving in all phenotypes. The prognosis is much better in the milder phenotypes, provided the therapeutic protocols are met.

GENE OR REGION STUDIED


  • ACADVL